Key Points
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A high frequency of T cells are alloreactive and are involved in transplant rejection and graft-versus-host disease (GVHD).
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Many alloreactive T cells are much more peptide specific than previously thought, and few if any recognize only the MHC molecule.
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Alloreactive T cells are polyspecific, being able to recognize multiple distinct peptide–MHC complexes. This provides a potential explanation for the high frequency of allorecognition.
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Structural studies of T-cell receptor (TCR)–peptide–MHC complexes reveal that alloreactive TCRs bind to peptide–MHC molecules in conventional ways and appear to exhibit similar diverse binding modes as conventional T cells.
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There is no single set of molecular interactions that reveals a germline-encoded preference of TCRs to bind MHC molecules, but there may be conserved contacts that differ for each TCR variable (V) region and MHC allele.
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Histocompatibility responses are important for marine colonial tunicates, allowing them to reject parasitic stem cells, but there is no selective advantage for alloreactivity in vertebrates. For vertebrates, alloreactivity may simply be the consequence of an inherent affinity of the TCR for the MHC molecule and a conserved surface among MHC alleles.
Abstract
T-cell alloreactivity is a well-established phenomenon, but its molecular basis has remained enigmatic. Although there are differences between T-cell recognition of conventional and allogeneic antigens, it has become increasingly clear that they share many similarities. Recent insights into the specificity of the T-cell receptor (TCR) for peptide and the seeming intrinsic affinity of the TCR for the surface of the MHC molecule have provided a better understanding of how the TCR and peptide–MHC complexes interact. Here, we highlight the similarities and differences between conventional and allogeneic recognition of TCR–peptide–MHC complexes, and discuss how our view of allorecognitionhas changed, as well as the implications for TCR specificity and T-cell development.
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References
Gorer, P. A. The genetic and antigenic basis of tumor transplantation. J. Pathol. Bacteriol. 44, 691–697 (1937).
Billingham, R. E., Brent, L. & Medawar, P. B. Actively acquired tolerance of foreign cells. Nature 172, 603–606 (1953).
Zinkernagel, R. M. & Doherty, P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248, 701–702 (1974).
Garcia, K. C. et al. An αβ T cell receptor structure at 2.5 Å and its orientation in the TCR–MHC complex. Science 274, 209–219 (1996).
Lindahl, K. F. & Wilson, D. B. Histocompatibility antigen-activated cytotoxic T lymphocytes. II. Estimates of the frequency and specificity of precursors. J. Exp. Med. 145, 508–522 (1977).
Suchin, E. J. et al. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J. Immunol. 166, 973–981 (2001).
Bevan, M. J. High determinant density may explain the phenomenon of alloreactivity. Immunol. Today 5, 128–130 (1984).
Matzinger, P. & Bevan, M. J. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell. Immunol. 29, 1–5 (1977). Reference 8 presents one of the early hypotheses on the basis of alloreactivity.
Whitelegg, A. M. et al. Investigation of peptide involvement in T cell allorecognition using recombinant HLA class I multimers. J. Immunol. 175, 1706–1714 (2005).
Weber, D. A. et al. Requirement for peptide in alloreactive CD4+ T cell recognition of class II MHC molecules. J. Immunol. 154, 5153–5164 (1995).
Udaka, K., Tsomides, T. J. & Eisen, H. N. A naturally occurring peptide recognized by alloreactive CD8+ cytotoxic T lymphocytes in association with a class I MHC protein. Cell 69, 989–998 (1992). In this paper, the authors report the identification of the first peptide involved in allorecognition.
Tallquist, M. D., Yun, T. J. & Pease, L. R. A single T cell receptor recognizes structurally distinct MHC/peptide complexes with high specificity. J. Exp. Med. 184, 1017–1026 (1996).
Pittet, M. J. et al. Ex vivo characterization of allo-MHC-restricted T cells specific for a single MHC-peptide complex. J. Immunol. 176, 2330–2336 (2006).
Panina-Bordignon, P., Corradin, G., Roosnek, E., Sette, A. & Lanzavecchia, A. Recognition by class II alloreactive T cells of processed determinants from human serum proteins. Science 252, 1548–1550 (1991).
Obst, R., Munz, C., Stevanovic, S. & Rammensee, H. G. Allo- and self-restricted cytotoxic T lymphocytes against a peptide library: evidence for a functionally diverse allorestricted T cell repertoire. Eur. J. Immunol. 28, 2432–2443 (1998).
Mendiratta, S. K. et al. Peptide dependency of alloreactive CD4+ T cell responses. Int. Immunol. 11, 351–360 (1999).
Malarkannan, S., Afkarian, M. & Shastri, N. A rare cryptic translation product is presented by Kb major histocompatibility complex class I molecule to alloreactive T cells. J. Exp. Med. 182, 1739–1750 (1995).
Kovalik, J. P. et al. The alloreactive and self-restricted CD4+ T cell response directed against a single MHC class II/peptide combination. J. Immunol. 165, 1285–1293 (2000).
Heath, W. R. & Sherman, L. A. Cell-type-specific recognition of allogeneic cells by alloreactive cytotoxic T cells: a consequence of peptide-dependent allorecognition. Eur. J. Immunol. 21, 153–159 (1991).
Heath, W. R., Kane, K. P., Mescher, M. F. & Sherman, L. A. Alloreactive T cells discriminate among a diverse set of endogenous peptides. Proc. Natl Acad. Sci. USA 88, 5101–5105 (1991). The authors in this study make the important observation that self peptides bound to MHC molecules are involved in alloreactivity.
Crumpacker, D. B., Alexander, J., Cresswell, P. & Engelhard, V. H. Role of endogenous peptides in murine allogenic cytotoxic T cell responses assessed using transfectants of the antigen-processing mutant 174xCEM.T2. J. Immunol. 148, 3004–3011 (1992).
Alexander-Miller, M. A., Burke, K., Koszinowski, U. H., Hansen, T. H. & Connolly, J. M. Alloreactive cytotoxic T lymphocytes generated in the presence of viral-derived peptides show exquisite peptide and MHC specificity. J. Immunol. 151, 1–10 (1993).
Huseby, E. S., Crawford, F., White, J., Kappler, J. & Marrack, P. Negative selection imparts peptide specificity to the mature T cell repertoire. Proc. Natl Acad. Sci. USA 100, 11565–11570 (2003).
Guimezanes, A. et al. Identification of endogenous peptides recognized by in vivo or in vitro generated alloreactive cytotoxic T lymphocytes: distinct characteristics correlated with CD8 dependence. Eur. J. Immunol. 31, 421–432 (2001).
Felix, N. J. et al. Alloreactive T cells respond specifically to multiple distinct peptide–MHC complexes. Nature Immunol. 8, 388–397 (2007). In this paper, the authors provide direct evidence for the polyspecificity of alloresponses.
Mazza, C. et al. How much can a T-cell antigen receptor adapt to structurally distinct antigenic peptides? EMBO J. 26, 1972–1983 (2007).
Housset, D. & Malissen, B. What do TCR–pMHC crystal structures teach us about MHC restriction and alloreactivity? Trends Immunol. 24, 429–437 (2003).
Wucherpfennig, K. W. et al. Polyspecificity of T cell and B cell receptor recognition. Semin. Immunol. 19, 215 (2007).
Reiser, J. B. et al. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nature Immunol. 4, 241–247 (2003). In this study the authors describe the structures of a single TCR bound to two distinct peptides presented by the same allogeneic MHC allele.
Jerne, N. K. The somatic generation of immune recognition. Eur. J. Immunol. 1, 1–9 (1971). This paper presents the first theory for the germline-encoded preference of TCRs for MHC molecules.
Zerrahn, J., Held, W. & Raulet, D. H. The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88, 627–636 (1997). This study provides direct experimental evidence in favour a germline-encoded preference of TCRs for MHC molecules.
Huseby, E. S. et al. How the T cell repertoire becomes peptide and MHC specific. Cell 122, 247–260 (2005). This paper demonstrates that negative selection is responsible for maintaining peptide specificity.
Lombardi, G., Barber, L., Sidhu, S., Batchelor, J. R. & Lechler, R. I. The specificity of alloreactive T cells is determined by MHC polymorphisms which contact the T cell receptor and which influence peptide binding. Int. Immunol. 3, 769–775 (1991).
Grandea, A. G., 3rd & Bevan, M. J. Single-residue changes in class I major histocompatibility complex molecules stimulate responses to self peptides. Proc. Natl Acad. Sci. USA 89, 2794–2798 (1992).
Basu, D., Horvath, S., O'Mara, L., Donermeyer, D. & Allen, P. M. Two MHC surface amino acid differences distinguish foreign peptide recognition from autoantigen specificity. J. Immunol. 166, 4005–4011 (2001).
Bluestone, J. A., Jameson, S., Miller, S. & Dick, R. 2nd. Peptide-induced conformational changes in class I heavy chains alter major histocompatibility complex recognition. J. Exp. Med. 176, 1757–1761 (1992).
Bluestone, J. A., Kaliyaperumal, A., Jameson, S., Miller, S. & Dick, R. 2nd. Peptide-induced changes in class I heavy chains alter allorecognition. J. Immunol. 151, 3943–3953 (1993).
Chattopadhyay, S., Theobald, M., Biggs, J. & Sherman, L. A. Conformational differences in major histocompatibility complex-peptide complexes can result in alloreactivity. J. Exp. Med. 179, 213–219 (1994).
Sherman, L. A., Chattopadhyay, S., Biggs, J. A., Dick, R. F. 2nd & Bluestone, J. A. Alloantibodies can discriminate class I major histocompatibility complex molecules associated with various endogenous peptides. Proc. Natl Acad. Sci. USA 90, 6949–6951 (1993).
Hulsmeyer, M. et al. HLA-B27 subtypes differentially associated with disease exhibit subtle structural alterations. J. Biol. Chem. 277, 47844–47853 (2002).
Macdonald, W. A. et al. A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition. J. Exp. Med. 198, 679–691 (2003).
Hennecke, J. & Wiley, D. C. Structure of a complex of the human α/β T cell receptor (TCR) HA1.7, influenza hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401): insight into TCR cross-restriction and alloreactivity. J. Exp. Med. 195, 571–581 (2002).
Chen, W., McCluskey, J., Rodda, S. & Carbone, F. R. Changes at peptide residues buried in the major histocompatibility complex (MHC) class I binding cleft influence T cell recognition: a possible role for indirect conformational alterations in the MHC class I or bound peptide in determining T cell recognition. J. Exp. Med. 177, 869–873 (1993).
Kersh, G. J. et al. Structural and functional consequences of altering a peptide MHC anchor residue. J. Immunol. 166, 3345–3354 (2001).
Luz, J. G. et al. Structural comparison of allogeneic and syngeneic T cell receptor-peptide-major histocompatibility complex complexes: a buried alloreactive mutation subtly alters peptide presentation substantially increasing Vβ interactions. J. Exp. Med. 195, 1175–1186 (2002).
Rudolph, M. G., Stanfield, R. L. & Wilson, I. A. How TCRs bind MHCs, peptides, and coreceptors. Annu. Rev. Immunol. 24, 419–466 (2006).
Frelinger, J. A. & McMillan, M. The role of peptide specificity in MHC class I-restricted allogeneic responses. Immunol. Rev. 154, 45–58 (1996).
Lechler, R. I., Lombardi, G., Batchelor, J. R., Reinsmoen, N. & Bach, F. H. The molecular basis of alloreactivity. Immunol. Today 11, 83–88 (1990).
Sherman, L. A. & Chattopadhyay, S. The molecular basis of allorecognition. Annu. Rev. Immunol. 11, 385–402 (1993).
Rotzschke, O., Falk, K., Faath, S. & Rammensee, H. G. On the nature of peptides involved in T cell alloreactivity. J. Exp. Med. 174, 1059–1071 (1991).
Elliott, T. J. & Eisen, H. N. Cytotoxic T lymphocytes recognize a reconstituted class I histocompatibility antigen (HLA-A2) as an allogeneic target molecule. Proc. Natl Acad. Sci. USA 87, 5213–5217 (1990).
Smith, P. A., Brunmark, A., Jackson, M. R. & Potter, T. A. Peptide-independent recognition by alloreactive cytotoxic T lymphocytes (CTL). J. Exp. Med. 185, 1023–1033 (1997).
Obst, R., Netuschil, N., Klopfer, K., Stevanovic, S. & Rammensee, H. G. The role of peptides in T cell alloreactivity is determined by self-major histocompatibility complex molecules. J. Exp. Med. 191, 805–812 (2000).
Colf, L. A. et al. How a single T cell receptor recognizes both self and foreign MHC. Cell 129, 135–146 (2007). In this paper, the crystal structure of a single TCR bound to a foreign and allogenic ligand is reported.
Matis, L. A., Sorger, S. B., McElligott, D. L., Fink, P. J. & Hedrick, S. M. The molecular basis of alloreactivity in antigen-specific, major histocompatibility complex-restricted T cell clones. Cell 51, 59–69 (1987).
Demotz, S. et al. Self peptide requirement for class II major histocompatibility complex allorecognition. Proc. Natl Acad. Sci. USA 88, 8730–8734 (1991).
Felix, N. J. et al. H2-DMα−/− mice show the importance of major histocompatibility complex-bound peptide in cardiac allograft rejection. J. Exp. Med. 192, 31–40 (2000).
Daniel, C., Horvath, S. & Allen, P. M. A basis for alloreactivity: MHC helical residues broaden peptide recognition by the TCR. Immunity 8, 543–552 (1998).
Crawford, F., Huseby, E., White, J., Marrack, P. & Kappler, J. W. Mimotopes for alloreactive and conventional T cells in a peptide-MHC display library. PLoS Biol. 2, e90 (2004).
Donermeyer, D. L., Weber, K. S., Kranz, D. M. & Allen, P. M. The study of high-affinity TCRs reveals duality in T cell recognition of antigen: specificity and degeneracy. J. Immunol. 177, 6911–6919 (2006).
Felix, N. J. et al. I-Ep-bound self-peptides: identification, characterization, and role in alloreactivity. J. Immunol. 176, 1062–1071 (2006).
Reiser, J. B. et al. Crystal structure of a T cell receptor bound to an allogeneic MHC molecule. Nature Immunol. 1, 291–297 (2000).
Wucherpfennig, K. W. T cell receptor crossreactivity as a general property of T cell recognition. Mol. Immunol. 40, 1009–1017 (2004).
Cohn, M. Degeneracy, mimicry and crossreactivity in immune recognition. Mol. Immunol. 42, 651–655 (2005).
Wilson, D. B. et al. Specificity and degeneracy of T cells. Mol. Immunol. 40, 1047–1055 (2004).
Maverakis, E., van den Elzen, P. & Sercarz, E. E. Self-reactive T cells and degeneracy of T cell recognition: evolving concepts-from sequence homology to shape mimicry and TCR flexibility. J. Autoimmun. 16, 201–209 (2001).
Hemmer, B., Vergelli, M., Pinilla, C., Houghten, R. & Martin, R. Probing degeneracy in T-cell recognition using peptide combinatorial libraries. Immunol. Today 19, 163–168 (1998).
Mason, D. A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol. Today 19, 395–404 (1998).
Cameron, D. J. & Erlanger, B. F. Evidence for multispecificity of antibody molecules. Nature 268, 763–765 (1977).
Keitel, T. et al. Crystallographic analysis of anti-p24 (HIV-1) monoclonal antibody cross-reactivity and polyspecificity. Cell 91, 811–820 (1997).
Appel, J. R., Buencamino, J., Houghten, R. A. & Pinilla, C. Exploring antibody polyspecificity using synthetic combinatorial libraries. Mol. Divers. 2, 29–34 (1996).
Stewart, A. K., Huang, C., Long, A. A., Stollar, B. D. & Schwartz, R. S. VH-gene representation in autoantibodies reflects the normal human B-cell repertoire. Immunol. Rev. 128, 101–122 (1992).
Ternynck, T. & Avrameas, S. Murine natural monoclonal autoantibodies: a study of their polyspecificities and their affinities. Immunol. Rev. 94, 99–112 (1986).
James, L. C., Roversi, P. & Tawfik, D. S. Antibody multispecificity mediated by conformational diversity. Science 299, 1362–1367 (2003).
James, L. C. & Tawfik, D. S. The specificity of cross-reactivity: promiscuous antibody binding involves specific hydrogen bonds rather than nonspecific hydrophobic stickiness. Protein Sci. 12, 2183–2193 (2003).
Crawford, F. et al. Use of baculovirus MHC/peptide display libraries to characterize T-cell receptor ligands. Immunol. Rev. 210, 156–170 (2006).
Holler, P. D., Chlewicki, L. K. & Kranz, D. M. TCRs with high affinity for foreign pMHC show self-reactivity. Nature Immunol. 4, 55–62 (2003).
Norbury, C. C. et al. CD8+ T cell cross-priming via transfer of proteasome substrates. Science 304, 1318–1321 (2004).
Wolkers, M. C., Brouwenstijn, N., Bakker, A. H., Toebes, M. & Schumacher, T. N. Antigen bias in T cell cross-priming. Science 304, 1314–1317 (2004).
Shen, L. & Rock, K. L. Cellular protein is the source of cross-priming antigen in vivo. Proc. Natl Acad. Sci. USA 101, 3035–3040 (2004).
Ackerman, A. L. & Cresswell, P. Cellular mechanisms governing cross-presentation of exogenous antigens. Nature Immunol. 5, 678–684 (2004).
Guermonprez, P. et al. ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 425, 397–402 (2003).
Houde, M. et al. Phagosomes are competent organelles for antigen cross-presentation. Nature 425, 402–406 (2003).
Nimmerjahn, F. et al. Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. Eur. J. Immunol. 33, 1250–1259 (2003).
Zhou, D. et al. Lamp-2a facilitates MHC class II presentation of cytoplasmic antigens. Immunity 22, 571–581 (2005).
Dengjel, J. et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc. Natl Acad. Sci. USA 102, 7922–7927 (2005).
Paludan, C. et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593–596 (2005).
Falk, K., Rotzschke, O., Stevanovic, S., Jung, G. & Rammensee, H. G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351, 290–296 (1991).
Hunt, D. F. et al. Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 255, 1261–1263 (1992).
Hunt, D. F. et al. Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Science 256, 1817–1820 (1992).
Chicz, R. M. et al. Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size. Nature 358, 764–768 (1992).
Dongre, A. R. et al. In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses. Eur. J. Immunol. 31, 1485–1494 (2001).
Suri, A. et al. In APCs, the autologous peptides selected by the diabetogenic I-Ag7 molecule are unique and determined by the amino acid changes in the P9 pocket. J. Immunol. 168, 1235–1243 (2002).
Lechler, R. I. & Batchelor, J. R. Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells. J. Exp. Med. 155, 31–41 (1982).
Gould, D. S. & Auchincloss, H. Jr. Direct and indirect recognition: the role of MHC antigens in graft rejection. Immunol. Today 20, 77–82 (1999).
Batista, F. D., Iber, D. & Neuberger, M. S. B cells acquire antigen from target cells after synapse formation. Nature 411, 489–494 (2001).
Huang, J. F. et al. TCR-Mediated internalization of peptide-MHC complexes acquired by T cells. Science 286, 952–954 (1999).
Hwang, I. et al. T cells can use either T cell receptor or CD28 receptors to absorb and internalize cell surface molecules derived from antigen-presenting cells. J. Exp. Med. 191, 1137–1148 (2000).
Lee, P. U., Churchill, H. R., Daniels, M., Jameson, S. C. & Kranz, D. M. Role of 2C T-cell receptor residues in the binding of self- and allo-major histocompatibility complexes. J. Exp. Med. 191, 1355–1364 (2000).
Borg, N. A. et al. The CDR3 regions of an immunodominant T cell receptor dictate the 'energetic landscape' of peptide–MHC recognition. Nature Immunol. 6, 171–180 (2005).
Tynan, F. E. et al. T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide. Nature Immunol. 6, 1114–1122 (2005). This paper reports on the recognition of conserved MHC residues by different TCRs and discusses the possibility of a 'restriction triad'.
Tynan, F. E. et al. A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule. Nature Immunol. 8, 268–276 (2007).
Hahn, M., Nicholson, M. J., Pyrdol, J. & Wucherpfennig, K. W. Unconventional topology of self peptide–major histocompatibility complex binding by a human autoimmune T cell receptor. Nature Immunol. 6, 490–496 (2005).
Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).
von Boehmer, H. et al. Thymic selection revisited: how essential is it? Immunol. Rev. 191, 62–78 (2003).
Buslepp, J., Wang, H., Biddison, W. E., Appella, E. & Collins, E. J. A correlation between TCR Vα docking on MHC and CD8 dependence: implications for T cell selection. Immunity 19, 595–606 (2003).
Maynard, J. et al. Structure of an autoimmune T cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity. Immunity 22, 81–92 (2005).
Feng, D., Bond, C. J., Ely, L. K., Maynard, J. & Garcia, K. C. Structural evidence for a germline-encoded T cell receptor-major histocompatibility complex interaction 'codon'. Nature Immunol. 8, 975–983 (2007). In this paper, the authors identify a conserved binding motif of one Vβ chain to MHC molecules, which introduces the concept of an interaction codon.
Reiser, J. B. et al. A T cell receptor CDR3β loop undergoes conformational changes of unprecedented magnitude upon binding to a peptide/MHC class I complex. Immunity 16, 345–354 (2002).
Reinherz, E. L. et al. The crystal structure of a T cell receptor in complex with peptide and MHC class II. Science 286, 1913–1921 (1999).
Fellouse, F. A. et al. Molecular recognition by a binary code. J. Mol. Biol. 348, 1153–1162 (2005).
Ely, L. K. et al. Disparate thermodynamics governing T cell receptor-MHC-I interactions implicate extrinsic factors in guiding MHC restriction. Proc. Natl Acad. Sci. USA 103, 6641–6646 (2006).
Bancroft, F. W. Variaton and fusion of colonies in compound ascidians. Proc. Calif. Acad. Sci. 3, 138–186 (1903).
Oka, H. Watanabe, H. Problems of colony specificity in compound ascidians. Bull. Biol. Stn. Asamushi 10, 153–155 (1960).
De Tomaso, A. W. et al. Isolation and characterization of a protochordate histocompatibility locus. Nature 438, 454–459 (2005).
Nyholm, S. V. et al. fester, A candidate allorecognition receptor from a primitive chordate. Immunity 25, 163–173 (2006).
Laird, D. J., De Tomaso, A. W. & Weissman, I. L. Stem cells are units of natural selection in a colonial ascidian. Cell 123, 1351–1360 (2005).
Messaoudi, I., Guevara Patino, J. A., Dyall, R., LeMaoult, J. & Nikolich-Zugich, J. Direct link between MHC polymorphism, T cell avidity, and diversity in immune defense. Science 298, 1797–1800 (2002).
Claas, F. H. et al. Differential immunogenicity of HLA mismatches in clinical transplantation. Transpl. Immunol. 14, 187–191 (2005).
Hwang, S. H. et al. Influence of mismatching of HLA cross-reactive groups on cadaveric kidney transplantation. Transplant. Proc. 37, 4194–4198 (2005).
Lo, A., Stratta, R. J., Alloway, R. R. & Hodge, E. E. A multicenter analysis of the significance of HLA matching on outcomes after kidney-pancreas transplantation. Transplant. Proc. 37, 1289–1290 (2005).
Malaise, J. et al. Effect of HLA matching in simultaneous pancreas-kidney transplantation. Transplant. Proc. 37, 2846–2847 (2005).
Sheldon, S. & Poulton, K. HLA typing and its influence on organ transplantation. Methods Mol. Biol. 333, 157–174 (2006).
Wade, J. A. et al. HLA mismatching within or outside of cross-reactive groups (CREGs) is associated with similar outcomes after unrelated hematopoietic stem cell transplantation. Blood 109, 4064–4070 (2007).
Chakraverty, R. et al. Host MHC class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions. Blood 108, 2106–2113 (2006).
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TCR–peptide–MHC structures discussed in this review. (PDF 187 kb)
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Glossary
- Self MHC molecules
-
This term refers to those MHC molecules that are encoded in an individual's genome and that are expressed by an individual's own antigen-presenting cells. These should be distinguished from the distinct donor- or graft-derived MHC alleles, which we refer to here as allogeneic MHC molecules.
- Conventional immune response
-
An immune response directed against peptides presented by self MHC molecules is frequently referred to as a conventional immune response. We adopt this terminology here to distinguish these immune responses from those directed against peptides presented by allogeneic MHC molecules (alloresponses).
- Self tolerance
-
Tolerance to an individual's own antigens that is achieved through both central and peripheral tolerance mechanisms including T-cell deletion, anergy and immune regulation. Without both central- and peripheral-tolerance mechanisms the immune system would be unable to distinguish self from foreign, resulting in autoimmunity.
- Alloreactivity
-
An immune response to allograft transplantation that is directed against allelic differences between the host and donor. For the purposes of this Review we focus almost entirely on T-cell receptor recognition of peptide–allogeneic-MHC complexes; although alloreactivity also includes B-cell-mediated responses and innate immune responses to allelic differences between host and donor. In addition, alloreactivity can occur as host-versus-donor or donor-versus-host responses (as occurs in graft-versus-host disease).
- Graft-versus-host disease
-
(GVHD). An immune response mediated by donor T cells contained in a transplanted allograft and directed against the recipient. GVHD is not associated with solid-organ transplantation, but can occur with bone-marrow or haematopoietic stem-cell transplants.
- Degeneracy
-
In the context of T-cell recognition of antigen, degeneracy refers to a situation in which there is a decrease in the number and strength of the interactions between the TCR and the bound peptide. As a result, there is less specificity for the bound peptide.
- Molecular mimicry
-
A term used to describe what happens when a T-cell receptor recognizes a microbial peptide that is structurally similar to a self peptide. The immune response initially directed at the microbial peptide spreads to tissues presenting the crossreactive self peptide, resulting in autoimmunity.
- Polyspecificity
-
A recently suggested term to describe the ability of a single receptor (for example, a T-cell receptor or antibody) to recognize multiple unique ligands while maintaining a high degree of specificity for each ligand.
- MHC class I tetramers
-
A tetrahedral complex artificially generated by joining four MHC class I molecules with a peptide of interest and β2-microglobulin. Because of their ability to interact with multiple T-cell recpetors (TCRs) at once, these tetramers are useful tools to detect specific binding despite the low affinity of individual TCR–peptide–MHC interactions.
- Peptide libraries
-
A random mixture of peptides generated by mixing all 20 amino acids (or a subset thereof) at single or multiple peptide residue positions during the synthesis process. The resulting peptide pool will contain a mixture of peptides of which the theoretical complexity is determined by the number of positions at which substitutions were allowed and by the number of substitutions allowed at each position. The generation of a peptide library is an efficient means to obtain a large pool of peptides without individually synthesizing each member of the peptide pool.
- Peptide mimotopes
-
A term generally used to refer to synthetic peptides of which the sequences have been empirically chosen based on their ability to mimic the response to the wild-type (and often unknown) peptide.
- Direct and indirect allorecognition
-
The T-cell-mediated immune response to allogeneic tissues or grafts can occur through direct recognition of peptide–allogeneic-MHC complexes by host T-cell receptors or by indirect recognition of donor antigens captured by host antigen-presenting cells and presented as allogeneic-peptide–self-MHC complexes.
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Felix, N., Allen, P. Specificity of T-cell alloreactivity. Nat Rev Immunol 7, 942–953 (2007). https://doi.org/10.1038/nri2200
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DOI: https://doi.org/10.1038/nri2200
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